Will Contrave Succeed Where Others Have Failed?

As part of the Year in Review series, MedPage Today reporters are revisiting major news stories and following up with an analysis of the impact of the original report, as well as subsequent news generated by the initial publication. Here's what's happened on the weight-loss drug front since we first published a 2010 piece on the topic.

After the FDA rejected two weight-loss medications, and another was pulled from the market, it appeared 2010 would be a bad year for diet drugs. But in December, an FDA advisory panel put the wheels in motion to give doctors another option in their never-ending battle to help obese patients lose weight.

If FDA gives its stamp of approval to Orexigen's naltrexone/bupropion (Contrave) and makes it the first new diet drug approved in a decade, will the drug work where others have failed and offer obese patients fewer side effects, and maybe, just maybe, reduce the deadly comorbidities that accompany obesity?

Or, will it go the way of failed weight-loss drugs of the past -- notably fenfluramine and phentermine (Fen-Phen) and sibutramine (Meridia) -- where modest weight loss achieved by patients paled in comparison with serious side effects that became evident after the drug had been on the market for a number of years?

"This is an encouraging development -- those of us involved with management of obesity are much in need of some new pharmacologic tools," Howard Eisenson, MD, executive director of the Duke Diet and Fitness Center in Durham, N.C., told ABC News/MedPage Today. "While this will not be a 'wonder drug,' research studies suggest that, if approved, it will be a significant help in dealing with this challenging problem."

Little Success With Diet Drugs

The problem is that about 27 million Americans are obese, which is defined as having a body mass index of over 30.

While the FDA has approved new drugs to prevent and treat comorbidities caused by obesity, there have been no new fat-fighting drugs approved in the past decade.

Two diet drugs have been removed from the market for serious health concerns (fenfluramine/phentermine and sibutramine) and two more have been rejected by the FDA in recent months (phentermine/topiramate and lorcaserin hydrochloride).

Fen-Phen, the popular fenfluramine/phentermine obesity drug, was pulled from the market about six months after its approval in 1997 because of an increased risk of heart valve problems.

In October, the maker of the obesity drug sibutramine (Meridia) voluntarily agreed to remove it from the U.S. market because of increased risk of stroke and MI. The move followed a split-down-the-middle FDA advisory panel vote in September. Half the 16 members voted that sibutramine remain on the market, albeit with certain new restrictions; the other half voted the drug down because weight loss with the drug did not balance out the potential cardiovascular side effects.

Later that month, the FDA rejected Arena Pharmaceuticals' application to approve its investigational weight-loss drug lorcaserin (Lorqess), citing a variety of concerns including a less than impressive average weight loss -- just 5% of baseline weight -- and data from animal studies suggesting that lorcaserin increased the risk of mammary adenocarcinoma in rats.

And the following week, the FDA rejected phentermine/topiramate (Qnexa). The drug, made by Vivus, was shown to be effective in helping obese and overweight patients lose an average of 6% to 10% of their body weight in the company's clinical trials -- one panelist said the drug is "far superior to anything on the market." However, concerns over psychiatric and cardiovascular issues uncovered in the company's clinical trials ultimately trumped the drug's weight-loss benefit.

Psychiatric adverse events -- including sleep disorders, anxiety, and depression -- occurred in 21% of patients taking the highest doses of the new drug, compared with 10% of patients taking placebo. Cardiovascular safety was also a prominent concern; data from the company's trials didn't indicate an increased risk of valvulopathy, although the drug did increase heart rate.

There is just one weight-loss drug still on the market: orlistat (Xenical, Alli).

Well-known Ingredients ...

Orexigen, which makes naltrexone/bupropion in partnership with Takeda, is seeking approval for treatment of obesity and weight management in patients with a body mass index of 30 or above, or 27 or above and with one or more risk factors (e.g., diabetes, dyslipidemia, or hypertension).

Contrave works by combining naltrexone, an anti-addiction drug prescribed for opioid addiction and alcohol dependence, and bupropion, used to treat depression and smoking cessation. Little is known about combining the drugs for weight loss.

"The good news is this: Both of these ingredients have been around for a while, but have never been used together," said Paul Doering, a pharmacy professor at the University of Florida in Gainesville, Fla. "Their track record of safety is comforting, but I remind you that Fen-Phen was a combination of two drugs that, separately, had been around quite a while."

... But Unimpressive Data

Orexigen's clinical trials were not all that impressive. Four placebo-controlled, one-year, phase III clinical trials of 3,200 obese patients all met one of the FDA's standards for weight-loss drugs -- that more than 30% of patients lose at least 5% of their body weight -- but they failed to meet another.

Patients on the naltrexone/bupropion combination lost more weight than the placebo group (P<0.001) -- but not by much. In a pooled analysis, naltrexone/bupropion patients lost an average of 4.2% more weight than the placebo group. That falls short of the other FDA standard: after one year, the difference in mean weight loss between the active and control groups should be at least 5%.

"Support for Contrave is less about how good this particular drug combination is (it's modestly effective and has some toxicity), and more about how bad the overall state of pharmacotherapy for weight management is," said David L. Katz, MD, MPH, director of the Yale University Prevention Research Center. "The FDA committee's decision can be justified by invoking the 'any port in a storm!' clause."

Naltrexone/bupropion was shown to raise blood pressure during the first eight weeks of treatment -- a concerning side effect to some panelists, who pointed out that a drug to help obese patients should lower blood pressure, just as losing weight lowers blood pressure.

But naltrexone/bupropion offered far fewer side effects than some other weight-loss drugs that have been on the market or in development.

Moreover, increased blood pressure is "not a terribly worrisome" because it's so easily monitored, said Henry Miller, MD, a former medical reviewer with the FDA and currently a researcher at Stanford University in Calif., studying pharmaceutical development.

The study failed to come out conclusively on the drug's cardiovascular risks, however.

"That's good news/bad news," said Miller. "The bad news is that the number of events was too small to be conclusive; the good news is that the (adverse) effect, if any, was not sufficiently large to see an effect with a fairly large number of patients."

Long-term Risks Unknown

There is possibility that more side effects of naltrexone/bupropion will emerge after patients take the drug for several years. There is currently no data showing how patients fare on the drug after taking it for more than a year.

"Yes, if things turn out badly, and there is a possible risk the drug would have to be pulled from the market, that's something we'd have to accept," said one of the panelists at advisory committee meeting, biostatistician David Oakes, PhD, of the University of Rochester in New York.

But Carla Wolper, a researcher at the New York Obesity Research Center at St. Luke's Hospital in New York City, said if the FDA approves naltrexone/bupropion, it would not be consistent with the agency's decision to withdraw sibutramine, which was also shown to raise blood pressure slightly.

"Perhaps FDA is getting the message that obese Americans need something short of major surgery to help them lose weight," Wolper said.

Just last week, an FDA device advisory committee endorsed lowering the BMI threshold for the stomach-shrinking Lap Band to as low as 30, making the surgery an option for additional millions of obese Americans.

The FDA will issue a final decision on naltrexone/bupropion by Jan. 31. The agency is not required to follow the advice of its advisory committees, but it often does.

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